Garlits built his first race car in 1954 beneath an oak tree at his North Tampa home, fashioning a T-bucket roadster from a 1927 Ford Model T fitted with a 1948 Mercury engine. That vehicle ran the quarter mile in 13.5 seconds at 93 mph. He converted it into his first rail-job dragster by stripping the body, moving the engine rearward, and repositioning the seat behind the drive axle — a slingshot configuration that won him his first NHRA event, the Safety Safari in Lake City, Florida, clocking 12.1 seconds at 108 mph.
By 1959 Garlits had become the sport's most prominent figure outside California, drawing over 30,000 spectators to the US Fuel and Gas Championships at Bakersfield — the largest drag-race crowd to that point. In 1964 he joined a contingent of American stars who traveled to England for the inaugural International Drag Festival, helping establish the sport in Europe.
On March 8, 1970, at Lions Drag Strip, Garlits was driving Swamp Rat XIII when the two-speed transmission he was developing exploded. The blast severed part of his right foot and broke the car in half directly in front of the cockpit. Sidelined for the season, Garlits drafted plans from a wheelchair for a fundamentally different machine: a rear-engined dragster that placed the driver ahead of the engine, fuel system, and drivetrain.
He returned in 1971 with Swamp Rat XIV. Despite initial skepticism from the rodding press about the unconventional layout, the car proved dominant. Garlits won two of his next three Top Fuel Eliminator titles — the Winternats and Bakersfield — and was runner-up at Lions. The rear-engine configuration eliminated the most common cause of fatal and crippling injuries to front-engined slingshot drivers and became the universal standard; every Top Fuel and Funny Car in professional drag racing has since adopted it.
Garlits was the first drag racer to officially surpass 170, 180, 200, 240, 250, and 270 mph in the quarter mile, and the first to exceed 200 mph in the eighth mile. These benchmarks, set over several decades of competition, established him as the defining performance figure in the sport's history.
In 1977 he switched from the 426 hemi he had used for thirteen years to the Donovan 417 cubic-inch engine, broadening the technical landscape of Top Fuel machinery. He returned to NHRA Top Fuel full-time in 1984 after a brief hiatus.
In May 2003, at age 71, Garlits qualified for the NHRA POWERade Series Southern Nationals in Atlanta, setting a personal best of 4.788 seconds at 319.98 mph and reaching 323.04 mph at that year's Gatornationals — making him one of the oldest drivers ever to qualify for an NHRA national event.
In May 2014 Garlits drove Swamp Rat 37, a 2,000 hp battery-electric dragster, to 184 mph, and in July 2019, at age 87, he piloted the 800 hp electric Swamp Rat 38 to a new personal best of 189.03 mph, demonstrating continued commitment to the sport's technological frontier.
Over his competitive career Garlits accumulated 17 major-sanctioning-body championships: ten American Hot Rod Association titles, four International Hot Rod Association titles, and three National Hot Rod Association titles. He won 144 national events in total. He was 54 years old when he claimed his final championship.
He temporarily retired in 1987 following a blowover at the AHRA World Finals in Spokane and worked as a color commentator for NHRA telecasts on TNN and NBC for four seasons. A detached retina — attributed to the 4g deceleration forces of Top Fuel braking parachutes — ended his 1992 comeback attempt. He made further returns in 1998 and 2003.
Garlits consistently placed driver protection at the center of his public advocacy. He championed the adoption of full-body Nomex fire suits — including gloves, socks, and balaclava — well before they became mandatory. Following Funny Car driver Scott Kalitta's fatal crash in June 2008, Garlits publicly supported the NHRA's decision to shorten Top Fuel and Funny Car races from a quarter mile to 1,000 feet. He subsequently argued for further horsepower and tire-width reductions to slow elapsed times while maintaining spectator appeal.
Garlits operates the Don Garlits Museum of Drag Racing in Ocala, Florida, adjacent to his home. His record-setting Swamp Rat XXX was enshrined in the National Museum of American History at the Smithsonian Institution in Washington, D.C. on October 20, 1987.
He was ranked first on the NHRA's Top 50 Drivers list covering 1951–2000, was inducted into the Motorsports Hall of Fame of America in 1989 as drag racing's sole representative, the International Motorsports Hall of Fame in 1997, the Automotive Hall of Fame in 2004, and the British Drag Racing Hall of Fame in 2014. ESPN ranked him 23rd on their all-time top drivers list in 2008.